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In the St. Jude Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed higher risk for below-average performance on a measure of sustained attention, but not on measures of intellectual functioning, academic skills, or memory. The risk of cognitive deficits correlated with treatment intensity but not with age at diagnosis or gender. These results underscore the need for longitudinal follow-up to better characterize the prevalence and magnitude of cognitive deficits following CNS-directed therapy with chemotherapy alone.[20]

ALL and cranial radiation

In survivors of ALL, cranial radiation therapy does lead to identifiable neurodevelopment late sequelae. Although these abnormalities are mild in some patients (overall IQ fall of approximately 10 points), those who have received higher doses at a young age may have significant learning difficulties.[21,22] Deficits in neuropsychological functions, such as visual-motor integration, processing speed, attention, and short-term memory are reported in children treated with 1800 cGy to 2400 cGy.[23,24] Girls and younger children are more vulnerable to cranial irradiation.[25,26,27] The decline in intellectual functioning appears to be progressive, showing more impairment of cognitive function with increasing time since radiation therapy.[28] When the neurocognitive outcome of radiation therapy and chemotherapy-only CNS regimens are directly compared, the evidence suggests a better outcome for those treated with chemotherapy alone although some studies show no significant difference.[29,30,31]

It should be noted that the phenotype of attention problems in ALL survivors appears to differ from developmental attention-deficit disorder, as few survivors demonstrate significant hyperactivity/impulsivity. By contrast, impairments in cognitive efficiency (information processing and short-term memory) and executive functioning (organization and planning) have been more often observed among ALL survivors treated with cranial radiation therapy, and have been observed in children at lower frequency among those treated with chemotherapy alone.[32]

ALL and chemotherapy–only CNS therapy

Most studies of chemotherapy-only CNS-directed treatment display good neurocognitive long-term outcomes. However, one review suggests modest effects on processes of attention, speed of information processing, memory, verbal comprehension, visual-spatial skills, and visual-motor functioning; global intellectual function was found to be preserved.[23,29,33,34,35] Few longitudinal studies evaluating long-term neurocognitive outcome report adequate data for a decline in global IQ after treatment with chemotherapy alone.[34,36] The academic achievement of ALL survivors in the long term seems to be generally average for reading and spelling with deficits mainly affecting arithmetic performance.[29,37,38] Further risk factors for poor neurocognitive outcome after chemotherapy-only CNS-directed treatment are younger age and female gender.[36,39] Time since diagnosis or treatment does not appear to have a similar influence on neurocognitive functioning as observed following cranial irradiation.